ABSTRACT American Indians (AIs) are disproportionately impacted by the current opioid epidemic. AIs experience an 88% higher prevalence of OUDs (1.5%) than the US general population (0.8%), and AIs are second only to non-Latinx whites in their experience of opioid overdose deaths (13.9 and 17.5 per 100,000, respectively). Fortunately, medication-assisted treatment (MAT; e.g., buprenorphine + naloxone) is highly effective for reducing opioid- related harm, including overdose, making it the gold-standard OUD treatment approach. A recent systematic review, however, showed a median retention of 56% at the NIDA-recommended 12-month treatment length. Further, most AIs with OUD do not attend traditional substance-use treatment (62%). This is concerning because treatment retention is strongly associated with mortality rate reduction. Although no studies have documented OUD treatment outcomes specific to AIs, research in Native communities has generally highlighted concerns about the cultural acceptability of the highly directive, Western medical substance-use treatment approaches (e.g., cognitive-behavioral therapy, 12-step programming) that are widely available. Further, previous research has indicated that AIs with substance use disorders want greater representation of Native staff and better integration of culturally adapted approaches in the services they receive. Culturally adapted approaches to treatment are associated with reductions in use and associated problems. However, there are currently no evidence-based, culturally adapted counseling approaches for AIs addressing MAT retention and opioid-related harm. Accordingly, we propose a 2-phase R61/R33 development and evaluation project in response to RFA-DA- 19-013 - ?Responding to Opioid Use Disorders (OUD) in Tribal Communities in the Context of SAMHSA and CDC Funding.? This project will leverage recent federal OUD treatment initiative funding (SAMHSA TI-18-016, CDC-RFA-OT18-18030101supp) as a platform for culturally adapting substance-use counseling focused on improving MAT retention and reducing opioid-related harm within the Cherokee Nation Health System (CNHS). The 2-year R61 Phase will entail 2 parts. First, we will conduct a mixed methods inquiry to inform research methods and the community-specific, cultural adaptation of an existing, efficacious, harm-reduction counseling approach. Second, we will manualize and pilot the resulting Counseling for Harm Reduction and Retention in MAT at Cherokee Nation (CHaRRM-CN) together with a community advisory board comprising CNHS providers, staff, and patients as well as researchers from Cherokee Nation, Washington State University, and the University of Washington. The subsequent, 3-year R33 Phase will entail a 2-arm RCT (N=160) conducted within CNHS testing the efficacy of CHaRRM-CN in improving 6-month MAT retention, reducing substance-related harm and illicit opioid use, and increasing Native enculturation compared to a services-as-usual control condition (i.e., cognitive behavioral treatment).